Process for the preparation of pyridine derivatives

ABSTRACT

Processes for preparing sulfoxides useful as drugs such as acid secretion inhibitors or antiulcer drugs or intermediates for the preparation of drugs in high yields, at high purities, and with safety. Specifically, a process for the preparation of sulfoxides (II) by oxidizing a thio ether (I) with a peroxoborate salt in the presence of an acid anhydride or a metal catalyst; and a process for the preparation of sulfoxides (II) by oxidizing a thio ether (I) with an N-halosuccinimide, 1,3-dihalo-5,5-dimethyl-hydantoin or dichloroisocyanuric acid salt in the presence of a base. In said formulae R 1  is hydrogen, methoxy or difluoromethoxy; R 2  is methyl or methoxy; R 3  is 3-methoxypropoxy, methoxy or 2,2,2-trifluoroethoxy; and R 4  is hydrogen or methyl

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP98/03113 which has an Internationalfiling date of Jul. 10, 1998, which designated the United States ofAmerica.

FIELD OF THE INVENTION

The present invention relates to a method for producing a sulfoxidewhich is useful as a medicament such as an inhibitor of gastric acidsecretion or an anti-ulcer agent or an intermediate for producingmedicaments, as described in JP-A 1-6270 (Example 32), JP-A61-50978(Example 2), JP-A54-141783 (Example 21), JP-A61-22079 etc., in a goodyield at a high purity with safety.

PRIOR ART

Conventionally, sulfoxide has been produced by oxidizing thioether withoxidants such as hydrogen peroxide, m-chloroperbenzoic acid,sodiumhypochlorite, and sodiumbromite, as described in JP-A 1-6270(EP-268956, U.S. Pat. No. 5,045,552), JP-A 61-50978 (EP-174726, U.S.Pat. No. 4,628,098), JP-A 54-141783 (EP-5129, U.S. Pat. No. 4,255,431)or JP-A 61-22079 (EP-166287, U.S. Pat. No. 4,758,579). (See thefollowing formula, wherein R¹ to R⁴ have the same meanings as describedbelow).

Among the above oxidants, from viewpoints of readiness in weighing,storage stability and reaction activity and the like, m-chloroperbenzoicacid is frequently used.

In Example 32 of JP-A 1-6270, for example, thioether is oxidized byusing 0.96 equivalent (on a purity basis) of m-chloroperbenzoic acid, toproduce sulfoxide at a yield of 80%, which is not an industriallysatisfactory yield.

Depending on the reaction conditions, disadvantageously, the reactiondoes not ceased at the stage of sulfoxide production but furtherproceeds to a side reaction where a part of the produced sulfoxide isfurthermore oxidized to sulfone as shown in the following reactionscheme. When sulfone is formed, there is a problem not only that theyield of the objective sulfoxide is reduced, but also that it isdifficult to separate and purify them, since there is a closeresemblance in physicochemical property between the two. (In theformula, R¹ to R⁴ have the same meanings as described below.)

In JP-A 1-6270 and the like, additionally, the oxidation is conducted indichloromethane (methylene chloride), but from a viewpoint ofenvironmental strategies, there is a problem that halogenatedhydrocarbon solvents can never be used industrially.

Additionally, since m-chloroperbenzoic acid is expensive, it isextremely disadvantageous from a viewpoint of the production cost. Stilladditionally, m-chloroperbenzoic acid is listed as a dangerous materialand therefore requires deep attention for the use and storage thereof,inconveniently for large-scale handling.

As has been described above, no industrially excellent method forproducing sulfoxide (II) has been established yet. Accordingly, a novelexcellent method for producing sulfoxide (II) has been required.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive investigations so as to solvethe above-mentioned problems. As a result, they have found that theobjective sulfoxide (II) can be produced in a good yield with noformation of a byproduct sulfone, safety, with no use of any halogenatedhydrocarbon solvent. Thus, they have accomplished the present invention.

The present invention is a method for producing sulfoxide (II)represented by the following formula (II):

(wherein R¹ to R⁴ have the same meanings as described below), whichcomprises the step of oxidizing thioether (I) represented by thefollowing formula (I):

(wherein R¹ represents hydrogen atom, methoxy group or difluoromethoxygroup; R² represents methyl group or methoxy group; R³ represents3-methoxypropoxy group, methoxy group or 2,2,2-trifluoroethoxy group;and R⁴ represents hydrogen atom or methyl group) with a). a perborate inthe presence of an acid anhydride or a metal catalyst, or b).N-halosuccinimide, 1,3-dihalo-5,5-dimethylhydantoin ordichloroisocyanurate in the presence of a base.

More specifically, thioether (I) is a compound which is identical to2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazoledescribed in JP-A 1-6270 (Example 31), the compound described in JP-A61-50978 (Example 1) (R¹=H, R²=CH₃, R³=H, R⁴=CH₂CF₃ and n=0; chemicalname:2-{[4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole),5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazoleas a precursor of the compound described in JP-A 54-141783 (Example 21)or5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylthio]-1H-benzimidazoleas a precursor of the compound described in JP-A 61-22079, and is astarting material of the present invention. All the compounds can beproduced by the methods described in each publication.

More specifically, sulfoxide (II) is identical to2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(general name: Rabeprazole free base) described in JP-A 1-6270 (Example32), the compound described in JP-A 61-50978 (Example 2) (R¹=H, R²=CH₃,R³=H, R⁴=CH₂CF₃ and n=1; general name: Lansoprazole; chemical name:2-{[4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole),5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole(general name: Omeprazole) described in JP-A 54-141783 (Example 21) or5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole(general name: Pantoprazole) described in JP-A 61-22079, and is theobjective compound of the present invention.

More specifically, sulfoxide (II) includes for example the followingcompounds:

The method of production of the present invention is now described indetail.

The present invention encompasses the embodiments a) and b) describedabove.

The embodiments a) and b) are described hereinafter.

The type of perborate which is an oxidant used in the embodiment a) isnot limited, but generally, the sodium perborate is preferable. Further,the perborate may occasionally form a hydrate at no limited hydrationquantity, and generally, tetrahydrate or monohydrate is preferable.Additionally, sodium perborate·tetrahydrate (NaBO₃.4H₂O; CASRegistration No. 10486-00-7) and sodium perborate·monohydrate(NaBO₃.H₂O; CAS Registration No. 10332-33-9) are commercially availableas reagents and industrial raw materials and the like.

The amount of perborate to be used is not also limited, but generally itis used in the range of from 0.8 to 1.7 equivalents, more preferablyfrom 0.85 to 1.6 equivalents and further preferably from 0.9 to 1.5equivalents to thioether (I).

The type of N-halosuccinimide which is an oxidant used in the embodimentb) is not also limited, but generally, N-chlorosuccinimide (CASRegistration No. 128-09-6) or N-bromosuccinimide (CAS Registration No.128-08-5) is preferable. Additionally, N-halosuccinimide is alsocommercially available as a reagent and an industrial raw material andthe like.

The amount of N-halosuccinimide to be used is not also limited, butgenerally it is used in the range of from 0.8 to 1.7 equivalents, morepreferably from 0.85 to 1.6 equivalents and further preferably from 0.9to 1.5 equivalents to thioether (I).

Next, the type of 1,3-dihalo-5,5-dimethylhydantoin used in theembodiment b) is not also limited, but generally,1,3-dichloro-5,5-dimethylhydantoin (CAS Registration No. 118-52-5) or1,3-dibromo-5,5-dimethylhydantoin (CAS Registration No. 77-48-5) ispreferable. Additionally, 1,3-dihalo-5,5-dimethylhydantoin is alsocommercially available as a reagent and an industrial raw material andthe like.

The amount of 1,3-dihalo-5,5-dimethylhydantoin is not also limited, butgenerally it is used in the range of from 0.3 to 1.0 equivalent, morepreferably from 0.35 to 0.9 equivalent, further preferably from 0.4 to0.8 equivalent to thioether (I).

The type of dichloroisocyanurate used in the embodiment b) is not alsolimited, but generally, sodium dichloroisocyanurate (CAS RegistrationNo. 2893-78-9) or potassium dichloroisocyanurate (CAS Registration No.2244-21-5) is preferable. Furthermore, the dichloroisocyanurate is alsocommercially available as reagents and industrial raw materials and thelike.

The amount of dichloroisocyanurate to be used is not limited, butgenerally it is used in the range of from 0.3 to 1.0 equivalent, morepreferably from 0.35 to 0.9 equivalent, further preferably from 0.4 to0.8 equivalent to thioether (I).

Next, the reaction is conducted in the presence of an acid anhydride ora metal catalyst in the embodiment a). The presence of any one of thetwo is satisfactory.

The acid anhydride in the embodiment a) is not limited so long as it isprepared by dehydrating together carboxylic acids which may be the sameor different, or by subjecting a bifunctional carboxylic acid todehydration within the molecule. More specifically, it includes forexample acetic anhydride, propionic anhydride, butyric anhydride,succinic anhydride, maleic anhydride, benzoic anhydride or phthalicanhydride or the like. Generally, using acetic anhydride and propionicanhydride brings about more excellent results.

The amount of the acid anhydride used is not also limited, but generallyit is used in the range of from 0.8 to 1.7 equivalents, more preferablyfrom 0.85 to 1.6 equivalents, further preferably from 0.9 to 1.5equivalents to thioether (I).

Additionally, the most preferable result can be observed when the amountof acid anhydride used is in the range of from 1.0 to 2.0 equivalents toa perborate and from 0.9 to 1.5 equivalents to thioether (I).

The metal catalyst in the embodiment a) specifically includes vanadiumpentaoxide (V₂O₅), vanadyl acetylacetonate ((CH₃COCHCOCH₃)₂VO),molybdenum oxide actylacetonate ((CH₃COCHCOCH₃)₂MoO₂), ammoniumheptamolybdate tetrahydrate ((NH₄)₆ Mo₇O₂₄.4H₂O), ammonium molybdate((NH₄)₂MoO₄), sodium vanadate (NaVO₃), titanium tetraisopropoxide (Ti[OCH(CH₃)₂]₄), titanium trichloride (TiCl₃), tellurium dioxide (TeO₂),selenium dioxide (SeO₂), methyl trioxorhenium (CH₃ReO₃) or tungstenoxide (WO₃), and vanadyl acetylacetonate is the most preferable.

The amount of the metal catalyst to be used is not limited, but the usein an amount of 0.05 to 0.15 equivalent to a perborate brings about apreferable result.

Next, in the embodiment b), reaction is conducted in the presence of abase. Herein, the base used in the embodiment b) is not limited so longas it is inert to thioether (I), sulfoxide (II) or oxidants, butgenerally, inorganic bases are preferable. More specifically, the baseincludes for example sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium phosphate,potassium phosphate, sodium hydrogenphosphate, sodium formate, potassiumformate, sodium acetate, potassium acetate and the like, andadditionally includes mixtures of two or more thereof.

The amount of base to be used is not limited, but generally, it rangesfrom 0.8 to 4.0 equivalents, more preferably 0.85 to 3.5 equivalents andfurther preferably 0.9 to 3.0 equivalents to N-halosuccinimide.

Additionally, the base is generally used in an amount of 0.4 to 2.0equivalents, more preferably 0.4 to 1.75 equivalents and furtherpreferably 0.4 to 1.5 equivalents to 1,3-dihalo-5,5-dimethylhydrantoinor dichloroisocyanurate.

For the reaction, any solvent inactive to thioether I, sulfoxide II,further the perborate salt in the embodiment a) or the oxidant or basein the embodiment b) may be used singly or in combination, with nolimitation. Generally in the embodiment a), methanol, ethanol, propanol,mixture solvents such as methanol/toluene, ethanol/toluene,propanol/toluene, water/methanol, water/ethanol, water/propanol andtoluene/dimethylformamide, or acetic acid brings about a preferableresults. Preferable results are brought about in the embodiment b), byusing one or more of N,N-dimethylformamide, acetonitrile, toluene,tetrahydrofuran, lower fatty acid esters and water. The solvent may be amixture.

As the solvent in the embodiment b), a combination of one or moresolvents selected from N,N-dimethylformamide, acetonitrile, toluene,tetrahydrofuran and lower fatty acid esters in the presence of water isfurther preferable, and it brings about more excellent results.

The amount of water to be used is not limited, but generally, it rangesin amount from 0.1 to 50 ml, more preferably 0.25 to 20 ml and furtherpreferably 0.5 to 10 ml per 1 g of thioether (I).

The lower fatty acid esters in the embodiment b) are not limited so longas they are formed by dehydrating together a lower fatty acid having 6or less carbon atoms and a lower alcohol having 6 or less carbon atoms.The concrete examples thereof include methyl formate, ethyl formate,propyl formate, butyl formate, amyl formate, methyl acetate, ethylacetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butylacetate, t-butyl acetate, n-amyl acetate, i-amyl acetate, sec-amylacetate, t-amyl acetate, n-butyl propionate, ethyl butyrate, i-propylbutyrate, methyl isobutyrate, ethyl isobutyrate, methyl valerate, ethylisovalerate, ethyl pivalate and the like. Ethyl acetate is morepreferable.

When the solvent is a mixture, the ratio of the mixed solvents is notlimited, but the reaction may be conducted at an optionally ratio of themixed solvents.

The amount of the solvent is not also limited, but generally, it rangesfrom 1 to 100 ml, more preferably from 5 to 50 ml, further preferablyfrom 10 to 30 ml per 1 g of thioether (I).

The reaction temperature is not also limited, but generally, thereaction is conducted at −50° C. to room temperature, more preferably at−40° C. to 10° C. in the embodiment a) and at −30° C. to 20° C. in theembodiment b), further preferably at −30° C. to 0° C. in the embodimenta) and at −20° C. to 10° C. in the embodiment b).

The sequence of adding the each reagent (raw material) for the reactionis not also limited, but the following sequence, for example, can bringabout more preferable results.

Embodiment a):

1. A perborate is suspended in a solvent, followed by the dropwiseaddition of an acid anhydride and stirring to prepare a homogeneousmixture, to which is added a solvent if necessary. The resultingsolution is added dropwise into a solution of thioether (I).

2. A perborate is added to and dissolved in an acid anhydride and asolvent, and the resulting solution is added dropwise into a solution ofthioether (I).

3. A perborate is added to and dissolved in a mixture solution of anacid anhydride and a solvent, and the resulting solution is addeddropwise into a solution of thioether (I).

4. A perborate is suspended in a solvent, followed by the dropwiseaddition of a mixture solution of an acid anhydride and a solvent. Then,the resulting solution is stirred to prepare a homogenous solution,which is then added dropwise into a solution of thioether (I).

5. A perborate is dissolved in a solvent, and the resulting solution isadded dropwise into a solution of thioether (I) and a metal catalyst.

6. A metal catalyst is added to a solution of thioether (I), followed bythe dropwise addition of a solution of a perborate.

Embodiment b):

1. A base is added to a solution or suspension of thioether (I), towhich is then added N-halosuccinimide at low temperature, followed bystirring.

2. A solution of thioether (I) and a base is added to a solution ofN-halosuccinimide at low temperature, followed by stirring.

3. A base solution is added dropwise into a solution of thioether (I)and N-halosuccinimide.

4. A base is added to a solution of thioether (I), followed by theaddition of 1,3-dihalo-5,5-dimethylhydantoin at low temperature andstirring.

5. A solution of thioether (I) and a base is added to a solution of1,3-dihalo-5,5-dimethylhydantoin at low temperature, followed bystirring.

6. A base solution is added dropwise into a solution of thioether (I)and 1,3-dihalo-5,5-dimethylhydantoin, followed by stirring.

7. A base is added to a solution of thioether (I), followed by theaddition of a dichloroisocyanurate and subsequent stirring.

8. A solution of thioether (I) and a base is added to a solution of adichloroisocyanurate at low temperature, followed by stirring.

9. A base solution is added dropwise into a solution of thioether (I)and a dichloroisocyanurate, followed by stirring.

In the practice of the procedures (1) to (9) described above, morepreferable results can be observed by confirming that the pH of thereaction solution is always at basicity, more preferably at pH 12 orhigher, under monitoring.

The reaction time varies, depending on the amount of the solvent used,the reaction temperature, the amount of a perborate used in theembodiment a), and the type and amount of an oxidant used in theembodiment b), but generally, the reaction is completed in about 30 minto 6 hr.

The treatment after the completion of the reaction is not also limited,and for example, sodium hydrosulfite and additionally adding reducingagents such as sodium hyposulfite and sodium thiosulfate in theembodiment b) to decompose excess reagents and, if necessary, adjustingthe pH of the aqueous layer and the aqueous layer is extracted with thesolvent. In the embodiment b), furthermore, the mixture is evaporated,or the resulting crystals are collected by filtration.

The resulting sulfoxide (II) can be purified by conventional methodssuch as crystallization, recrystallization, column chromatography andthe like.

If necessary, the sulfoxide (II) may be converted into a salt accordingto known methods.

Furthermore, Tetrahedron Letters, 29(24), 2967-2968, 1988 discloses areaction comprising oxidation of olefin with sodium perborate .tetrahydrate in the presence of an acetic anhydride in methylenechloride, to give epoxide or α,β-diol monoacetate, however the reactionis totally different from the reaction of the present inventioncomprising oxidation of thioether to give sulfoxide.

JP-A 54-141783 (EP-5129, U.S. Pat. No. 4,255,431) describes that thefollowing oxidants can be used for the oxidation of thioether intosulfoxide; nitric acid, hydrogen peroxide, peracid, perester, ozone,dinitrogen tetraoxide, iodobenzene, 1-chlorobenzotriazole, tert-butylhypochlorite, a complex of diazo-bicyclo[2,2,2]octane with bromine,sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid,ceric ammonium nitrate, bromine, chlorine and sulfuryl chloride, as wellas N-halosuccinimide. However, m-chloroperbenzoic acid which is aperacid is the only one specifically disclosed in the Examples of theabove-mentioned JP-A 54-141783. Any description that onlyN-halosuccinimide is specifically excellent among the above variousoxidants is never found in the entirety of the specification or anydescription suggesting the excellency is absolutely never found therein.Further, any description that the presence of a base is essential orpreferable is absolutely never found therein.

Accordingly, the description about oxidants in JP-A 54-141783 isregarded as a mere example of general oxidants, with no influence on thenovelty of the present invention.

In J. O. C., 33(10), 3976-7, 1968, the reaction which relates to theoxidation of sulfide (thioether) with N-halosuccinimide is described.However, the sulfide specifically disclosed in the reference includesonly six compounds, namely dimethyl sulfide, diethyl sulfide,di-n-propyl sulfide, dibenzyl sulfide, benzyl phenyl sulfide anddiphenyl sulfide, and is entirely different from the thioether (I) ofthe present invention in structure.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an HPLC chart showing that the2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) obtained in Example 1 has a high purity.

Consequently, to describe the present invention more in detail, Examplesand Referential Examples will be given below. However, it is needless tosay that the present invention is not limited thereto.

EXAMPLES Example 1 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpridin-2-yl]methylsufinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate 4H₂O (tetrahydrate) (3.06 g, 18.9 mmol, 97%) wassuspended in water (8 ml), and then, acetic anhydride (1.84 ml, 18.9mmol, 95%) was added dropwise thereto while the bulk temperature of themixture was kept at 20° C. The resulting mixture was then stirred forabout 5 min, to prepare a homogenous solution. Methanol (8 ml) wasfurther added thereto. The resulting solution was added dropwise into asolution (55 ml) of2-{[4-(2-methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole(referred to as Compound I hereinafter; 5.0 g, 14.6 mmol) intoluene/methanol (10:1) at −20° C. over about 30 min, and the resultingmixture was continued stirring at the same temperature. After about 2hr, the completion of the reaction was confirmed by HPLC. 10 ml of anaqueous 0.1 wt % sodium hydrosulfite solution was added to the resultingreaction mixture and then, it was continuously stirred at the sametemperature for 10 min. The reducibility of the mixture was confirmedwith potassium iodide starch paper, followed by adding a 2 M aqueoussolution of sodium hydroxide (10 ml) to adjust the solution to pH 8. Theaqueous layer and the organic layer was separated and then, the aqueouslayer was extracted with 20 ml of toluene. The organic layer was washedwith 15 ml of brine. The resulting organic layer was evaporated to afinal volume of 25 ml, followed by the addition of ethyl acetate (20ml), and the resulting solution was stirred at −20° C. for 1 hr tocrystallize. The resulting precipitates were filtered under reducedpressure, washed twice with 5 ml of toluene/ethyl acetate (1:1) solutionpre-cooled to −20° C., and dried under reduced pressure for 1 hr, togive the title compound (4.37 g, yield; 83.6%) as a white solid.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.83-2.09(s, 3H), 2.13(s, 3H), 3.34(s,3H), 3.52(t,J=6.2 Hz, 2H), 4.05(t,J-6.2 Hz, 2H), 4.79(s, 2H),6.70(d,J=5.7 Hz, 1H), 7.07-7.30(m, 2H), 7.30-7.60 (br-s, 2H),8.27(d,J=5.7 Hz, 1H).

Example 2 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (2.12 g, 13.8 mmol) was dissolved in 10 ml ofwater/methanol (1:1) solution containing of acetic anhydride (1.28 ml,13.8 mmol). The resulting solution was added dropwise into 66 ml of asolution of the Compound I (3.0 g, 8.73 mmol) in toluene/methanol (10:1)at −5° C. over about 40 min, and then the resulting mixture was stirredas it was at the same temperature. The reaction was followed by HPLC.1.5 hr after the dropwise addition, a 0.1 wt % aqueous solution ofsodium hydrosulfite solution (10 ml) was added thereto, and theresulting mixture was stirred as it was at the same temperature for 10min. The reductive activity of the solution was confirmed with potassiumiodide starch paper followed by adding a 2 M aqueous solution of sodiumhydroxide (8.6 ml) to adjust the solution to pH 8 and adding 40 ml ofwater. After separating the aqueous layer and the organic layer, theresulting organic layer was washed with water (20 ml). And then, it wasevaporated to a final volume of 15 ml, 15 ml of ethyl acetate was addedthereto, and the resulting mixture was stirred at −20° C. for 30min tocrystallize. The resulting precipitates were filtered under reducedpressure, washed with 10 ml of toluene/ethyl acetate (1:1) pre-cooled to−20° C., and dried under reduced pressure, to give the title compound(2.55 g, yield: 81.3%) as a white solid.

Example 3 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate 4H₂O (2.68 g, 17.42 mmol) was dissolved in a solution(10 ml) of water/methanol (1:1) containing acetic anhydride (1.60 ml,17.46 mmol). The resulting solution was added dropwise into a solution(66 ml) of the Compound I (3.0 g, 8.73 mmol) in toluene/methanol (10:1)at −5° C. over 24 min and the resulting mixture was continued stirringas it was at the same temperature. After about 30 min, the completion ofthe reaction was confirmed by HPLC. Subsequently, the same procedures asin the previous Example were conducted to give the title compound (2.45g, yield; 78.2%) as a white solid.

Example 4 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (3.35 g, 21.78 mmol) was dissolved in a solution(10 ml) of water/methanol (1:1) containing acetic anhydride (4.4 ml,45.3 mmol). The resulting solution was added dropwise into a solution(66 ml) of the Compound I (3.0 g, 8.73 mmol) in toluene/methanol (10:1)at −5° C. over 60 min and the resulting mixture was continued stirringas it was at the same temperature. About 2 hr later, the completion ofthe reaction was confirmed by HPLC. Subsequently, the same procedures asin the previous Example were conducted to give the title compound (2.48g, yield; 79.4%) as a white solid.

Example 5 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (3.06 g, 18.9 mmol) was dissolved in a mixture ofacetic anhydride (1.84 ml, 18.9 mmol)/water (8 ml). The resultingsolution was added dropwise into a solution (67 ml) of the Compound I(5.0 g, 14.6 mmol) in toluene/dimethylformamide (3:1) mixture at −20° C.over 60 min. The resulting mixture was then stirred as it was at thesame temperature. After about 2.5 hr, the completion of the reaction wasconfirmed by HPLC. Subsequently, the same procedures as in the previousExample were effected to obtain the title compound (4.26 g, yield;81.5%) as a white solid.

Example 6 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (3.06 g, 18.9 mmol) was dissolved in a mixture ofacetic anhydride (1.84 ml, 18.9 mmol)/water (8 ml). The resultingsolution was added dropwise into a solution (60 ml) of the Compound I(5.0 g, 14.6 mmol) in toluene/ethanol (5:1) at −20° C. over 50 minutes.The resulting mixture was then stirred as it was at the sametemperature. After about 2 hr, the completion of the reaction wasconfirmed by HPLC. Subsequently, the same procedures as in the previousExample were conducted to give the title compound (3.99 g, yield; 78.5%)as a white solid.

Example 7 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (30.6 g, 0.189 mol, 97%) was suspended in 80 ml ofwater. Amixture of acetic anhydride (18.4 ml, 0.189 mol, 95%) andmethanol (30 ml) was added dropwise thereto over about 20 min, while thebulk temperature of the mixture was kept at about 15° C. Then, theresulting mixture was stirred for about 10 min, to prepare a homogenoussolution. The solution was added dropwise into a solution (550 ml) ofthe Compound I (50.0 g, 0.146 mol) in toluene/methanol (10:1) at −20° C.over about 2.5 hr, and the resulting mixture was stirred as it was atthe same temperature for about 2 hr. The completion of the reaction wasconfirmed by HPLC. A solution of sodium hydrosulfite (5.5 g) in water(50 ml) was added thereto, and then stirred as it was at the sametemperature for 10 min. The reducibility of the solution was confirmedwith potassium iodide starch paper, followed by adding a 2 M aqueoussolution of sodium hydroxide (110 ml) was added thereto to adjust thesolution to pH 8. Ethyl acetate (300 ml), water (200 ml) and methanol(80 ml) were added thereto to separate the aqueous layer and the organiclayer. The organic layer was washed with 150 ml of brine and thenevaporated on a water bath at a temperature of 30° C. 150 ml of ethylacetate and 150 ml of toluene were added to the resulting residue todissolve the residue, and the resulting solution was stirred at −20° C.for 1 hr. The resulting precipitates were filtered under reducedpressure, washed with t-butyl methyl ether (50 ml) for three times, andthen dried under reduced pressure for 1 hr to give the title compound asa white powder (48.0 g, yield; 91.8%, an HPLC purity; 95.9%).

Conditions for HPLC Analysis

Solid phase: NUCLEOSIL₅C₁₈

Mobile phase: MeOH: phosphate buffer (pH 7)=3:2

Flow rate: 1.0 ml/min

Detector: UV detector (290 nm)

Example 8 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (3.06 g, 18.9 mmol) was suspended in 8 ml ofwater, followed by the dropwise addition of propionic anhydride (2.56ml, 18.9 mmol) over 3 min, and the resulting mixture was then stirredfor about 10 min, to prepare a homogenous mixture. 8 ml of methanol wasadded to the resulting mixture (at a bulk temperature of 22.6° C. to26.2° C.) and then, it was added dropwise into a solution (55 ml) of theCompound I (5.00 g, 14.6 mmol) in toluene/methanol (10:1) at −20° C.over 35 min. The resulting mixture was further stirred at the sametemperature for 1 hr. The same procedures as in the previous Examplewere effected to obtain the title compound (4.19 g, yield; 80.1%).

Example 9 Synthesis of 2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio}-benzimidazole (Lansprazole)

Sodium perborate.4H₂O (0.58 g, 3.68 mmol) was dissolved in a mixture ofacetic anhydride (0.365 ml, 3.68 mmol) and water (8 ml). The resultingsolution was added dropwise to a solution (30 ml) of2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio}benzimidazole(1.0 g, 2.83 mmol) in toluene/methanol (5:1) at 0° C. over 16 min. Theresulting mixture was continued stirring as it was at the sametemperature. After about 1.5 hr later, the completion of the reactionwas confirmed by HPLC. After stirring the mixture for further 1 hr, thebulk temperature was gradually raised to 10° C. and the resultingmixture was continued stirring for 4 hr. Then, the mixture was cooled to−15° C. and stirred for 20 min. The resulting crystals were collected byfiltration under reduced pressure. The crystals were washed with cooledtoluene (10 ml) for two times, and then dried under reduced pressure togive the title compound (0.82 g, yield; 78.4%)as a white powder.

M.p.: 170-172° C. (decomp.) ¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.20(s,3H), 4.80(s, 2H), 4.88(s, 2H), 6.98(d,J=5.6 Hz, 1H), 7.33-7.36(m, 2H),7.63(br-s, 2H), 8.18(d,J=5.6 Hz, 1H).

Example 10 Synthesis of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole(Omeprazole)

Sodium perborate 4H₂O (11.2 g, 73.0 mmol) was suspended in water (50ml), followed by the dropwise addition of a solution of acetic anhydride(6.87 ml, 73.0 mmol)/methanol (5.75 ml) at 15.4° C. over 6 minutes andthen, the mixture was stirred for about 13 min to prepare a homogenoussolution (bulk temperature; 15.4° C. to 19.4° C.). The resultingsolution was added dropwise to a solution (220 ml) of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole(20.0 g, 60.8 mmol) in toluene/methanol (10:1) at −20° C. over 2 hr. Theresulting mixture was further stirred at the same temperature for 1 hr.The resulting crystals were collected by filtration, washed for threetimes with water (20 ml) and washed twice with tert-butyl methyl ether(20 ml). The resulting crystals were dried, to give the title compound(17.8 g, yield; 85.0%) as a white solid.

¹H-NMR (400 MHz, CDCl₃); δ ppm) 2.20(s, 3H), 2.25(s, 3H), 3.68(s, 3H),3.86(s, 3H), 4.70(Abq, 2H, J=13.7 Hz), 6.98-7.00(m, 2H), 7.65(br-d, 1H,J=8.29 Hz), 8.24(s, 1H), 1.19(br-s, 1H).

Example 11 Synthesis of2-{[4-(3-methoxypropoxy)-3-methypyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (537 mg, 3.49 mmol) was dissolved in a mixture ofacetic anhydride (0.40 ml, 6.99 mmol) and water (10 ml). The resultingsolution was added dropwise into a mixture (21ml) of the compound I(1.00 g, 2.91 mmol) and vanadyl acetylacetonate ((CH₃COCHCOCH₃)₂VO, 77.3mg, 0.29 mmol) in methanol/toluene (20:1) at 4° C. over 40 min, and theresulting mixture was continued stirring as it was at the sametemperature. After about 40 min, the completion of the reaction wasconfirmed by HPLC, and subsequently, the same procedures as in theprevious Example were conducted to give the title compound (2.35 g,yield; 75.0%).

Example 12 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

Sodium perborate.4H₂O (1.61 g, 10.5 mmol) was dissolved in a mixture ofacetic acid (1.20 ml, 21.0 mmol) and water (30 ml). The resultingsolution was added dropwise into a mixture solution (63ml) of thecompound I (3.00 g, 2.91 mmol) and vanadyl acetylacetonate (232 mg, 0.87mmol) in methanol/toluene (20:1) at −5° C. over about 1 hr, and theresulting mixture was continued stirring as it was at the sametemperature. After about 5 hr, the completion of the reaction wasconfirmed by HPLC. Subsequently, the resulting mixture was treated bythe same procedures as in the previous Example to give the titlecompound (2.22 g, yield; 71.0%).

Examples 13 to 21 Oxidation with N-halosuccinimide Examples 22 to 25Oxidation with 1,3-Dihalo-5,5-dimethydantoin Example 26 Oxidation withDichloroisocyanurate

Condition for HPLC Analysis

Solid phase: NUCLEOSIL₅C₁₈(4.6 mm I.D×150 mm, 5 μm)

Mobile phase: MeOH/0.05M phosphate buffer (pH 7)=3:2

Flow rate: 1.0 ml/min

Temperature: 25° C.

Detector: UV detector at 290 nm

Example 13 Synthesis of2-{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

2-{[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole(5.0 g 14.6 mmol; referred to as Compound I hereinafter) was dissolvedin 20 ml of N,N-dimethylformamide, followed by the addition of a 2Naqueous solution of sodium hydroxide (18 ml). A solution (10 ml) ofN-chlorosuccinimide (2.71 g, 20.3 mmol) in N,N-dimethylformamide wasadded dropwise to the solution at −20° C. to −10° C. The reactionmixture was reacted at −15° C. to −7° C. for 1.5 hr. To the reactionmixture was added a 10% aqueous solution of sodium thiosulfate (5 ml),stirred for 2 min and then, a solution (60 ml) of ammonium acetate (23.1g) in water was added thereto. 60 ml of ethyl acetate and 10 g of sodiumchloride were added thereto to extract the reaction mixture, and theaqueous layer was further extracted with ethyl acetate (40 ml). Theorganic layers were combined, washed with a 15% aqueous solution ofsodium chloride (80 ml) for three times and then, the solvent wasevaporated. To the resulting oil was added 12 ml of ethyl acetate, 28 mlof hexane and 10 ml of toluene, followed by stirring at room temperaturefor 1 hr. The resulting crystals were collected by filtration, washedwith a solvent mixture (10 ml) of 30% ethyl acetate and hexane for twotimes and then, dried under reduced pressure, to give the title compound(4.7 g, yield; 90.6%) as grayish white crystals.

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 1.10(t,J=7.2 Hz, 3H), 2.13(s, 3H),3.50(q,J=7.2 Hz, 2H), 3.71(m, 2H), 4.16(m, 2H), 4.70(d,J=13.6 Hz, 1H),4.78(d,J=13.6 Hz, 1H), 6.96(d,J5.6 Hz, 1H), 7.28(m, 2H), 7.62(m, 2H),8.20(d,J=5.6 Hz, 1H).

Example 14 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole)(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in 20 ml ofacetonitrile, followed by the addition of a 2N aqueous solution ofsodium hydroxide (14.5 ml). To the resulting solution was added dropwisea solution (8 ml) of N-chlorosuccinimide (2.13 g, 16.0 mmol) inN,N-dimethylformamide at −18 ° C. to −8 ° C. The reaction mixture wasreacted at −15° C. to −0° C. for 1.5 hr. To the reaction mixture wasadded a 10% aqueous solution of sodium thiosulfate (5 ml), and stirredfor 2 min, followed by the addition of a solution (60 ml) of ammoniumacetate (10 g) in water. Ethyl acetate (60 ml) and sodium chloride (10g) were added thereto to extract, and further the aqueous layer wasextracted with ethyl acetate (40 ml). The organic layers were combined,washed with a 15% aqueous solution of sodium chloride (80 ml) for threetimes, and then the solvent was evaporated. Ethyl acetate (12 ml),hexane (28 ml) and toluene (12 ml) were added to the resulting oil, andthe resulting mixture was stirred at room temperature for 1 hr. Theresulting crystals were collected by filtration, washed with a solventmixture (10 ml) of 30% ethyl acetate and hexane for two times, and thendried under reduced pressure, to give the title compound (4.68 g, yield;90.0%) as white crystals.

Example 15 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in a solvent mixture oftoluene (20 ml) and acetonitrile (10 ml), followed by the addition of a2N aqueous solution of sodium hydroxide (14.5 ml). To the resultingsolution was added dropwise a solution (8 ml) of N-chlorosuccinimide(2.13 g, 16.0 mmol) in N,N-dimethylformamide at 0° C. to 9° C. Thereaction mixture was reacted at 0° C. to 15° C. for 1.5 hr. To thereaction mixture was added a 10% aqueous solution of sodium thiosulfate(5 ml) and stirred for 2 min, followed by the addition of a 2N aqueoussolution of sodium hydroxide (14.5 ml). After adding toluene (10 ml)thereto to separate the organic layer, acetic acid (2.2 ml) was added tothe aqueous layer to adjust it to pH 8.5. Ethyl acetate (60 ml) andsodium chloride (5 g) were added thereto to extract and further theaqueous layer was extracted with ethyl acetate (40 ml). The organiclayers were combined, washed with a 15% aqueous solution of sodiumchloride (80 ml) for three times and then the solvent was evaporated.Ethyl acetate (10 ml), toluene (10 ml) and t-butyl methyl ether (20 ml)were added to the resulting oil and the mixture was stirred at roomtemperature for 1 hr. The resulting crystals were collected byfiltration, washed with t-butyl methyl ether (10 ml) for two times, andthen dried under reduced pressure, to give the title compound (3.9 g,yield; 74.8%) as grayish white crystals.

Example 16 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in 20 ml oftetrahydrofuran, followed by the addition of a 2N aqueous solution ofsodium hydroxide (14.5 ml). To the resulting solution was added dropwisea solution (8 ml) of N-chlorosuccinimide (2.13 g, 16.0 mmol) inN,N-dimethylformamide at 0° C. to 9° C. The reaction mixture was reactedat 5° C. to 0 ° C. for 1 hr. To the reaction mixture was added 5 ml of a10% aqueous solution (5 ml) of sodium thiosulfate was added to thereaction mixture and stirred for 2 min, followed by the addition of a 2Naqueous solution (14.5 ml) of sodium hydroxide. 40 ml of toluene wasadded to separate the organic layer, 2.2 ml of acetic acid was added tothe aqueous layer to adjust it to pH 8.5. Ethyl acetate (60 ml) andsodium chloride (4 g) were added thereto to extract and further theaqueous layer was extract with ethyl acetate (40 ml). The organic layerswere combined, washed with a 15% aqueous solution of sodium chloride (80ml) for three times, and then the solvent was evaporated. Ethyl acetate(10 ml), toluene (10 ml) and t-butyl methyl ether (20 ml) were added tothe resulting oil, and stirred at room temperature for 1 hr. Theresulting crystals were collected by filtration, washed with t-butylmethyl ether (10 ml) for two times, and then dried under reducedpressure, to give the title compound (3.9 g, yield; 74.8%) as grayishwhite crystals.

Example 17 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in 20 ml ofacetonitrile, followed by the addition of a 2N aqueous solution ofsodium hydroxide (14.5 ml). To the resulting solution was added dropwisea solution (8.5 ml) of N-chlorosuccinimide (2.32 g, 17.4 mmol) inN,N-dimethylformamide at −5° C. to 5° C. During the dropwise addition,the pH of the reaction mixture was monitored, and a 2N aqueous solutionof sodium hydroxide (10 ml) was simultaneously added dropwise thereto soas not to lower the pH value of the reaction solution below pH 12. Afterthe completion of the dropwise addition, the mixture was reacted forfurther 45 min at −3° C. to 0° C. After adding a 10% aqueous solution ofsodium thiosulfate (10 ml) to the reaction mixture and stirring themixture for 2 min, water (60 ml) was added thereto. The resultingmixture was adjusted to pH 9.2, by adding about 2.5 ml of acetic acidthereto, followed by the addition of ethyl acetate (60 ml) and sodiumchloride (12 g) to extract. Further, the aqueous layer was extractedwith ethyl acetate (40 ml). The organic layers were combined, washedwith a 15% aqueous solution of sodium chloride (80 ml) for three times,and then the solvent was evaporated. Ethyl acetate (12 ml), hexane (28ml) and toluene (10 ml) were added to the resulting oil, and the mixturewas stirred at room temperature for 1 hr. The resulting crystals werecollected by filtration, washed with a solvent mixture (10 ml) of 30%ethyl acetate and hexane for two times, and the dried under reducedpressure, to give the title compound (4.76 g, yield; 91.3%) as grayishwhite crystals.

Example 18 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in 20 ml ofacetonitrile, followed by the addition of a 2N aqueous solution ofsodium hydroxide (14.5 ml). To the resulting solution was added dropwise8.5 ml of a solution of N-chlorosuccinimide (2.32 g, 17.4 mmol) inN,N-dimethylformamide at −5° C. to 5° C. During the dropwise addition,the pH of the reaction solution was monitored, and 10 ml of a 2N aqueoussolution of sodium hydroxide (10 ml) solution was simultaneouslydropwise added to the reaction solution so as not to lower the pH valueof the reaction solution below pH 12. After the termination of thedropwise addition, the reaction solution was reacted at −3° C. to 0° C.for further 45 min. To the reaction mixture was added a 10% aqueoussolution of sodium thiosulfate (10 ml), stirred for 2 min and then, theacetonitrile was evaporated. The resulting solution was adjusted to pH9.1, by adding 85 ml of water and about 1.2 ml of acetic acid to thesolution, followed by stirring at 4° C. for 12 hr. The resultingcrystals were collected by filtration, washed with water (20 ml) forthree times and dried under reduced pressure, to give the title compound(3.97 g, yield; 76.2%) as grayish white crystals.

Example 19 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.6 mmol) was suspended in 20 ml ofacetonitrile, followed by the addition of a 2N aqueous solution ofsodium hydroxide (14.5 ml). To the resulting solution was added dropwise8.5 ml of a solution of N-chlorosuccinimide (2.32 g, 17.4 mmol) inN,N-dimethylformamide at −5° C. to 5° C. During the dropwise addition,the pH of the reaction solution was monitored, and a 2N aqueous solutionof sodium hydroxide (10 ml) was simultaneously dropwise added to thereaction solution so as not to lower the pH value of the reactionsolution below pH 12. After the completion of the dropwise addition, thereaction solution was reacted at −3° C. to 0° C. for further 45 min. Tothe reaction mixture was added a 10% aqueous solution of sodiumthiosulfate (10 ml), stirred for 2 min and then, 60 ml of water wasadded thereto. The resulting solution was adjusted to pH 9.2, by addingabout 1.3 ml of acetic acid to the solution, followed by the addition of50 ml of isopropyl acetate and 50 ml of hexane. Then, the resultingmixture was stirred at 4° C. for 12 hr. The resulting crystals werecollected by filtration, washed with 10 ml of a solvent mixture of 30%isopropyl acetate and hexane, and dried under reduced pressure, to givethe title compound (3.47 g, yield; 66.6%) as grayish white crystals.

Example 20 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (15.0 g, 43.7 mmol) was suspended in 75 ml ofacetonitrile, followed by the addition of 75 ml of a 2N aqueous solutionof sodium hydroxide. To the resulting solution was added dropwiseN-chlorosuccinimide (6.42 g, 48 mmol) little by little at −5° C. Thereaction mixture was reacted at −5° C. for 1.5 hr. To the reactionmixture was added 5 ml of a 1 H aqueous solution of sodium thiosulfatesolution, followed by stirring for 2 min and washing with toluene (10ml) for two times. Subsequently, 4.2 g of formic acid was added to theaqueous layer at 5° C., to adjust the aqueous layer to pH 9.0. Theresulting mixture was stirred as it was at the same temperature forabout 15 hr, and then the resulting slurry was filtered. The resultingsolid was dried, to give the title compound (14.00 g, yield; 89.2%,purity; 99.8%) as white crystals

Example 21 Synthesis of2-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Lansoprazole)

2-{[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio}-1H-benzimidazole(1.0 g, 2.83 mmol) was suspended in 8 ml of acetonitrile, followed bythe addition of 3.5 ml of a 2N aqueous solution of sodium hydroxide. Asolution (2 ml) of N-chlorosuccinimide (453 mg, 3.40 mmol) inN,N-dimethylformamide was added dropwise to the solution at −4° C. to 3°C. The reaction mixture was subsequently reacted at −3° C. to 0° C. for1.5 hr. To the reaction mixture was added a 10% aqueous solution ofsodium thiosulfate (2 ml) was added to the reaction mixture and theresulting mixture was stirred for 2 min, followed by the addition ofwater (20 ml) and acetic acid (0.4 ml) to adjust the solution to aboutpH 8.5. Ethyl acetate (20 ml) and sodium chloride (3 g) were addedthereto to extract and the aqueous layer was further extracted withethyl acetate (10 ml). The organic layers were combined, washed with a15% aqueous solution of sodium chloride (10 ml) for three times, and thesolvent was evaporated. Ethyl acetate (3 ml), hexane (7 ml) and toluene(2.5 ml) were added to the resulting oil, and then stirred at roomtemperature for 1 hr. The resulting crystals were collected byfiltration, washed with a solvent mixture (3 ml) of 30% ethyl acetateand hexane for two times, and then dried under reduced pressure, to givethe title compound (0.88 g, yield; 84.1%) as grayish white crystals.¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 2.16(s, 3H), 4.74(d,J=13.7 Hz, 1H),4.87(d,J=13.7 Hz, 1H), 4.88(d,J=8.8 Hz, 1H), 4.91(d,J=8.8 Hz, 1H),7.08(d,J=5.9 Hz, 1H), 7.29(m, 2H), 7.56(m, 1H), 7.70(m, 1H),8.27(d,J=5.9 Hz, 1H), 13.55(s, 1H).

Example 22 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (10.0 g, 29.1 mmol) was dissolved in 80 ml ofdimethylformamide, followed by the addition of a solution of potassiumhydrogen carbonate (2.91 g, 29.1 mmol) in water (20 ml). The resultingmixture solution was stirred under ice-cooling. At the same temperature,a solution of 1,3-dichloro-5,5-dimethylhydantoin (4.01 g, 20.37 mmol) indimethylformamide (15 ml) was added dropwise thereinto over 3 min, andstirred as it was at the same temperature for 70 min. Additionally,1,3-dichloro-5,5-dimethylhydantoin (0.34 g; 8.73 mmol) was added to theresulting mixture, and then it was stirred for 40 min. An aqueoussolution (10 ml) of sodium hyposulfite (5.13 g, 40.74 mmol) was added tothe resulting mixture, stirred for 5 min, and then a 2M aqueous solutionof sodium hydroxide (6 ml) was added thereto to adjust the solution topH 8. Water (80 ml) was added thereto, and the resulting aqueous layerwas extracted with ethyl acetate (200 ml) for two times and with 100 mlthereof once, and the extracted aqueous layers were combined together.The organic layer was washed with a 10% aqueous solution of brine fortwo times. The organic layer was evaporated, and to the resultingresidue were added ethyl acetate (30 ml), toluene (30 ml) and n-hexane(30 ml), and the resulting mixture was stirred at −15° C. for 11 hr. Theresulting crystals were filtered under reduced pressure, washed witht-butyl ethyl ether (25 ml) for two times and then dried to give thetitle compound (7.33 g, yield; 70.0%, an HPLC purity; 98.9%) as a whitesolid.

Example 23 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (10.0 g, 29.1 mmol) was dissolved in 80 ml ofdimethylformamide, followed by the addition of a solution (20ml) ofsodium hydrogen carbonate (2.46 g, 29.2 mmol) in water. The resultingmixture was stirred under ice-cooling. At the same temperature, asolution (20 ml) of 1,3-dichloro-5,5-dimethylhydantoin (4.01 g, 20.37mmol) in dimethylformamide was added dropwise thereinto over 10 min andstirred at the same temperature for 80 min. Further,1,3-dichloro-5,5-dimethylhydantoin (115 mg, 0.58 mmol) was added theretoand stirred for 20 min. A 1.0 M aqueous solution of sodium thiosulfate(30 ml) was added thereto and stirred for 5 min. Then, 30 ml of brinewas added thereto and the extracted with ethyl acetate (100 ml×2). Theorganic phase was rinsed in 100 ml of an aqueous 15% sodium chloridesolution and in 15 ml thereof and concentrated under reduced pressure.Toluene (15 ml), ethyl acetate (15 ml) and t-butyl methyl ether (15 ml)were added to the resulting residue, and the mixture was stirred at −10°C. for 13 hr. The resulting crystals were filtered under reducedpressure, washed with t-butyl methyl ether (50 ml) for two times, andthen dried, to give the title compound (7.05 g, yield; 67.0%) as a whitesolid.

Example 24 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.5 mmol) was dissolved in 25 ml of ethylacetate, followed by the addition of a solution of sodiumhydrogencarbonate (3.21 g, 32.1 mmol) in water (25 ml). The resultingmixture solution was stirred under ice-cooling. At the same temperature,1,3-dichloro-5,5-dimethylhydantoin (2.87 g, 14.6 mmol) was addedthereto, and then stirred for 2 hr. Additionally, the resulting mixturewas stirred at −10° C. for 30 min. The resulting crystals were filteredunder reduced pressure, washed with water (10 ml×2) and t-butyl methylether (10 ml×2), and then dried, to give the title compound (2.79 g,yield; 53.3%, an HPLC purity; 98.8%) as white crystals.

Example 25 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (10.0 g, 29.1 mmol) was dissolved in 40 ml of ethylacetate, followed by the addition of a solution of sodiumhydrogencarbonate (13.9 g, 140 mmol) in water (55 ml). The resultingmixture was stirred at −5° C. At the same temperature, a solution of 1,3-dichloro-5,5-dimethylhydantoin (6.88 g, 34.92 mmol) in ethyl acetate(60 ml) added thereto. After stirring for 2 hr, a 10% aqueous solutionof sodium hydrosulfite (50 ml) was added, and then stirred for 10 min. Amixture solution (110 ml) of n-hexane/toluene (1:1) was added theretoand the resulting mixture was stirred at −20° C. for 1.5 hr. Theresulting crystals were collected by filtration, washed with water (50ml×4) and t-butyl methyl ether (25 ml×2), and then dried, to give thetitle compound (7.09 g, yield; 68%, an HPLC purity; 98.2%) as whitecrystals.

Example 26 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base)

The Compound I (5.0 g, 14.5 mmol) was dissolved in 20 ml ofacetonitrile, followed by the addition of a 2M aqueous solution ofsodium hydroxide (29.1 ml). The resulting mixture solution was stirredat −15° C. At the same temperature, a solution of sodiumdichloroisocyanurate (2.24 g, 10.2 mmol) in water (15 ml) was addeddropwise thereinto over 10 min. During the addition, the temperature ofthe reaction mixture was raised from −15° C. to −5.6° C. After stirringfor 15 min at the same temperature, a solution (5 ml) of sodiumhydrosulfide (0.50 g) in water was added thereto, stirred for 30 min,and the insoluble matters were filtered off. The filtrate was adjustedto pH 7, by adding about 3 ml of formic acid thereto. The aqueous layerwas extracted with ethyl acetate (25 ml) once and with 10 ml thereofonce. The organic layer was washed with brine (10 ml) and evaporated.Ethyl acetate (20 ml), toluene (12 ml) and n-hexane (20 ml) were addedto the resulting residue, followed by stirring at −15° C. for 11 hr. Theresulting crystals were filtered under reduced pressure, washed witht-butyl methyl ether (20 ml) for two times, and then dried, to give thetitle compound (3.71 g, yield; 70.8%, an HPLC purity; 97.3%) as paleyellowish white crystals.

Next, to show the excellent effect of the present invention, ReferenceExamples in which the oxidants (nitric acid, sodium metaperiodate)disclosed in JP-A 54-141783 are used as comparative controls, and sodiumborate and sodium chlorate are used as other oxidants, to produce thesulfoxide (II) of the present invention.

The oxidants except the above oxidants disclosed in JP-A 54-141783 aredisadvantageously unstable, dangerous (explosive), unavailable at largevolume and expensive, and cause pollution. Thus, these oxidants are notapplicable as industrial raw materials.

REFERENTIAL EXAMPLES Referential Example 1 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:nitric acid)

The Compound I (2 g, 5.82 mmol) was dissolved in 20 ml of methanol,followed by the dropwise addition of 61% nitric acid (0.6 g, 5.82 mmol)at room temperature. After the dropwise addition, reacting the resultingmixture at room temperature for 2 hr. Subsequently, the change of thereaction mixture was confirmed by TLC (methanol/ethyl acetate=1/6; referto the same hereinafter). Consequently, no formation of the titlecompound was observed.

Referential Example 2 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:sodium metaperiodate)

The Compound I (2 g; 5.82 mmol) was dissolved in 50 ml of methanol andthe solution was cooled to 0° C. After cooling, sodium metaperiodate(1.26 g, 5.82 mmol) dissolved in water (25 ml) was added dropwisethereto. After the dropwise addition, reacting the mixture at roomtemperature for 22 hr. Subsequently, the change of the reaction mixturewas confirmed by TLC. Consequently, no formation of the title compoundwas confirmed.

Referential Example 3 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:sodium bromate)

The Compound I (2 g, 5.82 mmol) was dissolved in 30 ml of dioxane,followed by the dropwise addition of sodium bromate (1.69 g, 8.14 mmol)dissolved in water (5 ml). After the dropwise addition, reacting themixture at room temperature for 1.5 hr. Subsequently, the change of thereaction mixture was confirmed by TLC. Consequently, no formation of thetitle compound was observed.

Reference Example 4 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:sodium bromate)

The Compound I (2 g, 5.82 mmol) was dissolved in 40 ml of methanol,followed by the dropwise addition of sodium bromate (1.69 g, 8.14 mmol)dissolved in water (20 ml). After the dropwise addition, reacting themixture at room temperature for 16 hr. Subsequently, the change of thereaction mixture was confirmed by TLC. Consequently, no formation of thetitle compound was observed.

Referential Example 5 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:sodium chlorate)

The Compound I (5 g, 14.6 mmol) was dissolved in a solvent mixture ofethyl acetate (75 ml), methanol (25 ml) and water (30 ml), followed bythe dropwise addition of a 5% aqueous solution of sodium chlorate (22 g,14.6 mmol) at 5° C. 1 hr after the dropwise addition, the change of thereaction mixture was confirmed. Consequently, the formation of a slightamount of the title compound at a slight amount was confirmed, but greatquantities of byproducts were also observed, although no raw materialsremained.

Referential Example 6 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:manganese dioxide)

The Compound I (1 g, 2.9 mmol) was dissolved in dichloromethane (10 ml),followed by the addition of active manganese oxide (5 g) at roomtemperature. After reacting at room temperature for 21 hr, the change ofthe reaction solution was confirmed by HPLC. Consequently, no formationof the title compound was confirmed.

Referential Example 7 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:pyridinium dichromate)

The Compound I (1 g, 2.9 mmol) was dissolved in dichloromethane (10 ml),followed by the addition of pyridinium dichromate (1.1 g, 2.9 mmol) atroom temperature. After reacting at room temperature for 21 hr, thechange of the reaction mixture was confirmed by HPLC. Consequently, theformation of 3.2% (yield) of the title compound was confirmed but 96% ofthe Compound I still remained unreactive.

Referential Example 8 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(Rabeprazole free base) (oxidant:cerium diammonium nitrate)

The Compound I (1 g, 2.9 mmol) was suspended in a solvent mixture ofacetonitrile (20 ml) and water (10 ml), and then, cerium diammoniumnitrate (1.59 g, 2.9 mmol) was added dropwise thereinto. After reactingat room temperature for 20 hr, the change of the reaction mixture wasconfirmed by HPLC. Consequently, the formation of 0.5% of the titlecompound was observed, but 98% of the Compound I still remainedunreactive

The above results apparently indicate that the objective sulfoxide (II)can be obtained in a good yield and safety by the present invention.

Additionally, the cost of perborate, specifically sodiumperborate.tetrahydrate, is about {fraction (1/10)}-fold the cost ofm-chloroperbenzoic acid, so the present invention is extremely excellentin the respect of the production cost.

Further, perborate, specifically, sodium perborate.tetrahydrate,N-halosuccinimide, 1,3-dihalo-5,5-dimethylhydantoin anddichloroisocyanurate are not dangerous materials and are also handledeasily at a greater amount. Thus, the present invention is proved to bean industrially excellent method for producing sulfoxide (II).

What is claimed is:
 1. A method for producing a sulfoxide (II)represented by the following formula (II):

(wherein R¹, R², R³ and R⁴ have the same meanings as defined below),which comprises the step of oxidizing a thioether (I) represented by thefollowing formula (I):

(wherein R¹ represents hydrogen atom, methoxy group or difluoromethoxygroup; R² represents methyl group or methoxy group; R³ represents3-methoxypropoxy group, methoxy group or 2,2,2-trifluoroethoxy group;and R⁴ represents hydrogen atom or methyl group) with a) a perborate inthe presence of an acid anhydride or a metal catalyst or b) anN-halosuccinimide, a 1,3-dihalo-5,5-dimethylhydantoin ordichloroisocyanurate in the presence of a base.
 2. The method as claimedin claim 1, which comprises the step of oxidizing with a) a perborate inthe presence of an acid anhydride or a metal catalyst.
 3. The method asclaimed in claim 2, wherein the perborate is sodium perborate.
 4. Themethod as claimed in claim 2, wherein the perborate is sodium perboratetetrahydrate or sodium perborate monohydrate.
 5. The method as claimedin claim 2, wherein the perborate is used in an amount of 0.9 to 1.5equivalents to the thioether (I).
 6. The method as claimed in claim 2,wherein the oxidative reaction is conducted in methanol, ethanol,propanol and mixture solvents such as methanol/toluene, ethanol/toluene,propanol/toluene, water/methanol, water/ethanol, water/propanol andtoluene/dimethylformamide or acetic acid.
 7. The method as claimed inclaim 2, which is conducted in the presence of the acid anhydride. 8.The method as claimed in claim 7, wherein the acid anhydride is at leastone selected from the group consisting of acetic anhydride, propionicanhydride, butyric anhydride, succinic anhydride, maleic anhydride,benzoic anhydride and phthalic anhydride.
 9. The method as claimed inclaim 7, wherein the acid anhydride is used in an amount of 0.9 to 1.5equivalents to the thioether (I).
 10. The method as claimed in claim 7,wherein the acid anhydride is used in an amount of 1.0 to 2.0equivalents to the perborate, and of 0.9 to 1.5 equivalents to thethioether (I).
 11. The method as claimed in claim 2, which is conductedin the presence of the metal catalyst.
 12. The method as claimed inclaim 11, wherein the metal catalyst is at least one selected from thegroup consisting of vanadium pentaoxide, vanadyl acetylacetonate,molybdenum oxide actylacetonate, ammonium heptamolybdate tetrahydrate,ammonium molybdate, sodium vanadate, titanium tetraisopropoxide,titanium trichloride, tellurium dioxide, selenium dioxide, methyltrioxorhenium and tungsten oxide.
 13. The method as claimed in claim 11,wherein the metal catalyst is used in an amount of 0.05 to 0.15equivalent to the perborate.
 14. The method as claimed in claim 1, whichcomprises the step of oxidizing with b) N-halosuccinimide,1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate in the presenceof a base.
 15. The method as claimed in claim 14, wherein theN-halosuccinimide is N-chlorosuccinimide or N-bromosuccinimide.
 16. Themethod as claimed in claim 14, wherein the N-halosuccinimide is used inan amount of 0.9 to 1.5 equivalents to the thioether (I).
 17. The methodas claimed in claim 14, wherein the 1,3-dihalo-5,5-dimethylhydantoin is1,3-dichloro-5,5-dimethylhydantoin or 1,3-dibromo-5,5-dimethylhydantoin.18. The method as claimed in claim 14, wherein the1,3-dihalo-5,5-dimethylhydantoin is used in an amount of 0.4 to 0.8equivalent to the thioether (I).
 19. The method as claimed in claim 14,wherein the dichloroisocyanurate is sodium dichloroisocyanurate orpotassium dichloroisocyanurate.
 20. The method as claimed in claim 19,wherein the dichloroisocyanurate is used in an amount of 0.4 to 0.8equivalent to the thioether (I).
 21. The method as claimed in claim 14,wherein the base is an inorganic base.
 22. The method as claimed inclaim 21, wherein the base is at least one selected from the groupconsisting of sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, sodium phosphate, potassium phosphate,sodium hydrogen phosphate, sodium formate, potassium formate, sodiumacetate and potassium acetate.
 23. The method as claimed in claim 21,wherein the base is used in an amount of 0.9 to 3.0 equivalents to theN-halosuccinimide, and of 0.4 to 1.5 equivalents to the1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate salt.
 24. Themethod as claimed in claim 14, wherein the oxidation is conducted in thesolvent at least one selected from the group consisting ofN,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, lowerfatty acid esters and water.
 25. The method as claimed in claim 14,wherein the oxidation is conducted in a solvent at least one selectedfrom the group consisting of N,N-dimethylformamide, acetonitrile,toluene, tetrahydrofuran and lower fatty acid esters, in the presence ofwater.
 26. The method as claimed in claim 1, wherein the amount ofperborate is in the range of 0.8 to 1.7 equivalents to thioether (I).27. The method as claimed in claim 1, wherein the amount ofN-halosuccinimide is 0.8 to 1.7 equivalents to thioether (I).
 28. Themethod as claimed in claim 1, wherein the amount of1,3-dihalo-5,5-dimethylhydantoin is in the range of 0.3 to 1.0equivalent to thioether (I).
 29. The method as claimed in claim 1,wherein the amount of dichloroisocyanurate is in the range of 0.3 to 1.0equivalent to thioether (I).
 30. The method as claimed in claim 1,wherein the amount of acid anhydride is in the range of 0.8 to 1.7equivalents to thioether (I).
 31. The method as claimed in claim 1,wherein the amount of metal catalyst is 0.05 to 0.15 equivalent toperborate.
 32. The method as claimed in claim 1, wherein the amount ofbase is 0.8 to 4.0 equivalents to N-halosuccinimide.
 33. The method asclaimed in claim 1, wherein the amount of base is 0.4 to 2.0 equivalentsto 1,3-dihalo-5,5-dimethylhydrantoin or dichloroisocyanurate.
 34. Themethod as claimed in claim 24, wherein the amount of water is in therange of 0.1 to 50 ml per 1 g of thioether (I).
 35. The method asclaimed in claim 24, wherein the amount of solvent ranges from 1 to 100ml per 1 g of thioether (I).